As of 2017, over 100 million adults in the US has diabetes. Foot ulcers occur as a consequence of an open wound and is one of the leading causes of hospitalization for people with diabetes in the developed world and a major morbidity associated with diabetes leading to pain, suffering, and a poor quality of life for the patients. Around 26 million patients with diabetes in US alone develop foot ulcers at some point in their lives, costing approximately 25 billion dollars in care annually and accounting for about ~67% of all lower extremity amputations in the US. Bacterial infection has long been recognized as a major impediment to wound healing in diabetic ulcers. The underlying reasons for the inability of people with diabetic wounds to fight off bacterial infection remain poorly understood. Based on our preliminary studies we found 1) that neutrophil infiltration into diabetic wounds is delayed soon after injury, 2) once the neutrophils enter the wound, there is a delay in the release of chemokine to recruit inflammatory cells, and 3) neutrophils are unable to kill efficiently in diabetic wounds so that bioactive microbial products are not released in order to activate the infiltrated phagocytic leukocytes. Hence, our central hypothesis is that soon after injury in diabetic patients, impaired neutrophil chemotactic response, insufficient chemokine expression, and decreased microbial killing in diabetic wound lead to delayed inflammatory responses which underlie impaired infection control in the wound. In this proposal, we will: (Aim 1) determine the signaling mechanism(s) underlying impaired neutrophil chemotactic response to chemokines in diabetic wound; and (Aim 2) assess the underlying reason(s) for insufficient chemokine expression and microbial killing in the diabetic wound early after injury. We will also determine the potential of pro-inflammatory chemokines and Toll-like receptor ligands to restore antimicrobial defenses and stimulate healing by triggering the neutrophil response in diabetic wounds early after injury. These studies will advance our understanding of impaired infection control in diabetic wounds and lay the groundwork for novel therapeutic approaches to enhance antimicrobial defenses and to stimulate healing in diabetic wounds.